Synthesis of α-amino ketones from terminal alkynes via rhodium-catalyzed denitrogenative hydration of N -sulfonyl-1,2,3-triazoles

Article abstract of DOI:10.1021/ja2104203

N-Sulfonyl-1,2,3-triazoles react with water in the presence of a rhodium catalyst to produce α-amino ketones in high yield. An intermediary α-imino rhodium(II) carbenoid undergoes insertion into the O-H bond of water. This transformation formally achieves 1,2-aminohydroxylation of terminal alkynes in a regioselective fashion when combined with the copper(I)-catalyzed 1,3-dipolar cycloaddition with N-sulfonyl azides.

Full text of DOI:10.1021/ja2104203

Communication
pubs.acs.org/JACS
Synthesis of α-Amino Ketones from Terminal Alkynes via Rhodium-
Catalyzed Denitrogenative Hydration of N-Sulfonyl-1,2,3-triazoles
Tomoya Miura, Tsuneaki Biyajima, Tetsuji Fujii, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
S
* Supporting Information
of α-diazo imines, which are formed by ring−chain
ABSTRACT: N-Sulfonyl-1,2,3-triazoles react with water
in the presence of a rhodium catalyst to produce α-amino
ketones in high yield. An intermediary α-imino rhodium-
(II) carbenoid undergoes insertion into the O−H bond of
water. This transformation formally achieves 1,2-amino-
hydroxylation of terminal alkynes in a regioselective
fashion when combined with the copper(I)-catalyzed 1,3-
dipolar cycloaddition with N-sulfonyl azides.
tautomerization. We envisaged that the insertion of α-imino
metal carbenoids into the O−H bond of water16 would result in
the formation of α-imino alcohols (tautomers of α-amino
ketones), constituting a denitrogenative hydration reaction of
N-sulfonyl-1,2,3-triazoles. Thus, various transition-metal cata-
lysts were examined in the reaction of 4-phenyl-1-(N-tosyl)-
1,2,3-triazole (1a) with water. Whereas the use of nickel(0) and
copper(II) complexes led to the formation of complex
mixtures, the desired reaction proceeded under reaction
conditions using rhodium(II) complexes that were originally
reported for the nitrile insertion;13a when a chloroform solution
of 1a and water (10 equiv) in the presence of Rh2(Oct)4 (0.5
mol %, Oct = octanoate) was heated at 140 °C for 15 min
under microwave irradiation (MW),17 2-tosylamino-1-phenyl-
ethanone (2a) was produced in 91% isolated yield (Table 1,
entry 1). Substrates 1b−g possessing a variety of aryl groups,
also prepared from the corresponding terminal alkynes by the
1,3-dipolar cycloaddition reaction, all reacted facilely with water
to afford the corresponding products 2b−g in yields of 89−
94% (entries 2−7). Whereas 1-cyclohexenyl-substituted sub-
strate 1h successfully participated in the hydration reaction to
give the product 2h in 92% yield (entry 8), cyclohexyl-
substituted substrate 1i afforded the product 2i in only 26%
yield (entry 9). This was because β-hydride migration
preferentially occurred with the rhodium carbenoid intermedi-
ate to give α,β-unsaturated N-tosyl imine 3i (62%).13a,c,18
However, we found that when Rh2(t-BuCO2)4 (0.5 mol %) was
used under basic aqueous conditions [KOH (1.0 equiv) and
water (50 equiv) in chloroform (0.05 M)], the formation of 3i
decreased considerably and the yield of 2i increased to 78%
(entry 10). Remarkably, this modified system was also effective
for primary-alkyl-substituted substrates 1j−m, affording the
products 2j−m in high yield (entries 11−14). The reaction of
unsubstituted substrate 1n afforded α-amino aldehyde 2n,
albeit in low yield; 2n was unstable toward silica gel
and therefore was converted to the corresponding 2-amino
alcohol 4n for isolation by treatment with NaBH4 in wet
ethanol (entry 15).
α-Amino ketones constitute an important class of biologically
active compounds. For example, they are key substructures of
bupropion1 and brephedrone,2 which are used in the clinical
treatment of psychological disorders. α-Amino ketones also
serve as valuable intermediates for the synthesis of 2-amino
alcohols3 and various nitrogen-containing heterocycles.4 There-
fore, the development of new methods for synthesizing α-
amino ketones from readily available materials is highly
desired.5−9 We report herein a rhodium(II)-catalyzed deni-
trogenative hydration reaction of N-sulfonyl-1,2,3-triazoles that
opens a new synthetic route leading to α-amino ketones from
terminal alkynes. Formally, this transformation achieves
regioselective 1,2-aminohydroxylation of terminal alkynes,
providing a complement to the one reported by Chang10 and
Fokin11 using a copper(I) catalyst in terms of regioselectivity
(Figure 1).
Figure 1. Two pathways for the formal aminohydroxylation of terminal
alkynes.
Next, the variation of the sulfonyl group of 1 was examined
in the reaction with water using Rh2(Oct)4 as the catalyst
(Table 2). 4-Methoxybenzenesulfonyl, 4-bromobenzenesulfon-
yl, and 2-naphthalenesulfonyl triazoles 1o−q were similarly
reactive, furnishing α-amino ketones 2o−q in high yield
(entries 1−3). Not only arylsulfonyl groups but also
N-Sulfonyl-1,2,3-triazoles have become readily accessible
materials since the copper-catalyzed 1,3-dipolar cycloaddition
reaction of N-sulfonyl azides with terminal alkynes was
reported in 2007.12 Subsequently, a few groups developed
their transformations in which the diazo group was replaced
by organic molecules such as nitriles, alkynes, alkenes, and
alkanes.13−15 Rhodium(II) and nickel(0) catalysts generate high-
ly reactive α-imino metal carbenoids through denitrogenation
Received: November 5, 2011
Published: November 30, 2011
© 2011 American Chemical Society
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Journal of the American Chemical Society
Communication
Table 1. Rh(II)-Catalyzed Denitrogenative Hydration
Reaction of 4-Substituted 1-(N-Tosyl)-1,2,3-triazoles 1a−m
Table 2. Rh(II)-Catalyzed Denitrogenative Hydration
Reaction of 4-Phenyl 1-(N-Sulfonyl)-1,2,3-triazoles 1o−u
a
a
b
R1
2
yield (%)
b
entry
1
R2
2
yield (%)
entry
1
1
2
1a
1b
1c
1d
1e
1f
Ph
2a
2b
2c
2d
2e
2f
91
89
94
92
90
90
91
92
1
2
3
4
5
6
7
1o
1p
1q
1r
1s
1t
4-MeOC6H4
4-BrC6H4
2-naphthyl
Me
2o
2p
2q
2r
2s
2t
98
86
90
95
93
93
99
4-MeC6H4
4-PhC6H4
4-MeOC6H4
4-CF3C6H4
4-EtO2CC6H4
3-thienyl
3
4
5
n-Bu
6
Bn
7
1g
1h
1i
2g
2h
2i
1u
Me3Si(CH2)2
2u
8
1-cyclohexenyl
Cy
a
Conditions: 1 (0.20 mmol) and H2O (2.0 mmol, 10 equiv) in CHCl3
(4 mL) were heated at 140 °C for 15 min in the presence of
Rh2(Oct)4 (1.0 μmol) under microwave irradiation. Isolated yields
c
9
26
d
b
10
11
12
13
14
15
1i
Cy
2i
78
d
1j
n-Hex
2j
88
(averages of 2 runs).
d
1k
1l
(CH2)4OBz
(CH2)4OTBS
(CH2)4N(phth)
H
2k
21
2m
4n
93
d
Subsequent insertion of A into the O−H bond of water leads
to the formation of α-imino alcohol B,16 regenerating the
rhodium(II) catalyst. Finally, imine−enamine tautomerization
furnishes α-amino enol C, and keto−enol tautomerization
follows to give α-amino ketone 2.
To obtain mechanistic insights, an analogous reaction was
carried out using tert-butyl alcohol (5) instead of water (eq 2).
94
d
1m
1n
89
e
38
a
Conditions: 1 (0.20 mmol) and H2O (2.0 mmol, 10 equiv) in CHCl3
(4 mL) were heated at 140 °C for 15 min in the presence of Rh2(Oct)4
(1.0 μmol) under microwave irradiation, unless otherwise noted.
b
c
Isolated yields (averages of 2 runs). 3i was formed in 62% yield.
d
Using Rh2(t-BuCO2)4 (1.0 μmol) under basic aqueous conditions
[KOH (0.2 mmol) and H2O (10 mmol, 50 equiv) in CHCl3 (4 mL)].
e
The reaction was worked up with NaBH4 (0.20 mmol) in 3:2 EtOH/
α-Amino enol ether 6a was isolated in 56% yield along with
α-amino ketone 2a (21%). The formation of 6a can also be
explained by assuming that the carbenoid insertion into the
O−H bond of 5 is followed by imine−enamine tautomerization.
A one-pot synthesis of α-amino ketones starting from
terminal alkynes was carried out to demonstrate the practical
convenience of the present method (Table 3). Treatment of
terminal alkynes (7, 1.0 equiv) with tosyl azide (1.0 equiv) in
the presence of CuTC (10 mol %, TC = thiophene-2-
carboxylate) generated N-sulfonyl-1,2,3-triazoles 1.12b Next,
water (10 equiv), Rh2(Oct)4 (0.5 mol %), and chloroform
were added to the reaction mixture, which was further stirred
at 140 °C for 15 min under microwave irradiation. The
corresponding α-amino ketones 2 were isolated in overall yields
of 52−79%. In addition, the one-pot reaction was successfully
executed using only water as the solvent, although a higher
loading of the rhodium(II) catalyst was required (eq 3). It is
H2O (4.5 mL).
alkylsulfonyl groups were suitable; methyl, n-butyl, benzyl, and
2-(trimethylsilyl)ethylsulfonyl triazoles 1r−u were all compe-
tent substrates (entries 4−7). Thus, the reaction was highly
general with respect to the R2 substituent on the sulfonyl group.
This denitrogenative hydration reaction operated without
any problem when only water was used as the solvent in the
presence of the nonionic amphiphile PTS19 (eq 1).
A plausible mechanism for the production of 2 from 1 and
water is depicted in Scheme 1. Initially, a ring−chain
tautomerization of N-sulfonyl-1,2,3-triazole 1 generates α-
diazo imine 1′,20 although the equilibrium lies far to the left.
Diazo tautomer 1′ reacts with rhodium(II) with release of
molecular dinitrogen to give α-imino rhodium carbenoid A.
Scheme 1. Plausible Mechanism for the Formation of 2 from
1 and Water
noteworthy that molecular dinitrogen is the only waste product
in this sequential transformation.
In conclusion, the present method, when combined with the
copper(I)-catalyzed 1,3-dipolar cycloaddition of N-sulfonyl
azides with terminal alkynes, formally achieves 1,2-amino-
hydroxylation of terminal alkynes in a regioselective fashion,
which is difficult to execute with hitherto known methods.
195
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Journal of the American Chemical Society
Communication
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b
entry
7
R1
2
yield (%)
1
2
3
4
5
7a
7g
7h
7i
Ph
2a
2g
2h
2i
79
63
52
3-thienyl
1-cyclohexenyl
Cy
c
65
c
7j
n-Hex
2j
79
a
Conditions: A solution containing 7 (0.20 mmol), tosyl azide (0.20
mmol), and CuTC (20 μmol) in CHCl3 (1 mL) was stirred at rt for 6
h, and then H2O (2.0 mmol, 10 equiv) and Rh2(Oct)4 (1.0 μmol) in
CHCl3 (3 mL) were added. The resulting mixture was heated at
140 °C for 15 min under microwave irradiation. Isolated yields
(averages of 2 runs). Using Rh2(t-BuCO2)4 (1.0 μmol) under basic
b
c
aqueous conditions [KOH (0.20 mmol) and H2O (10 mmol, 50 equiv)
in CHCl3 (3 mL)].
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
murakami@sbchem.kyoto-u.ac.jp
ACKNOWLEDGMENTS
■
This work was supported in part by MEXT [Grants-in-Aid for
Scientific Research on Innovative Areas (22105005 and
22106520) and Young Scientists (A) (23685019)] and Asahi
Glass Foundation.
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